Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning.

The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

Predisposition to and effects of methamphetamine use on the adolescent brain.

Adolescence is a period of heightened vulnerability both to addictive behaviors and drug-induced brain damage. Yet, only limited information exists on the brain mechanisms underlying these adolescent-specific characteristics. Moreover, distinctions in brain correlates between predisposition to drug use and effects of drugs in adolescents are unclear. Using cortical thickness and diffusion tensor image analyses, we found greater and more widespread gray and white matter alterations, particularly affecting the frontostriatal system, in adolescent methamphetamine (MA) users compared with adult users. Among adolescent-specific gray matter alterations related to MA use, smaller cortical thickness in the orbitofrontal cortex was associated with family history of drug use. Our findings highlight that the adolescent brain, which undergoes active myelination and maturation, is more vulnerable to MA-related alterations than the adult brain. Furthermore, MA-use-related executive dysfunction was greater in adolescent MA users than in adult users. These findings may provide explanation for the severe behavioral complications and relapses that are common in adolescent-onset drug addiction. Additionally, these results may provide insights into distinguishing the neural mechanisms that underlie the predisposition to drug addiction from effects of drugs in adolescents.

Efficacy and tolerability of mirtazapine in treating major depressive disorder with anxiety symptoms: an 8-week open-label randomised paroxetine-controlled trial.

AIMS: Prominent anxiety symptoms are related to poor clinical course and outcome in major depressive disorder (MDD). The aim of this randomised, open-label, controlled study is to compare the efficacy and tolerability of mirtazapine in the form of orally disintegrating tablets against paroxetine in treating MDD patients with anxiety symptoms. METHODS: A total of 60 MDD patients with a score above 18 on the Hamilton Anxiety Rating Scale (HARS) were randomly assigned to 8 weeks of fixed dosing treatment with mirtazapine (15-30 mg/day) and paroxetine (10-20 mg/day). Efficacy was primarily assessed with the HARS and with the 17-item Hamilton Depression Rating Scale (HDRS) at weeks 1, 2, 4 and 8 after treatment. Tolerability was assessed from adverse events. RESULTS: The generalised estimating equations (GEE) models showed that the rates of improvement in HDRS scores from baseline to week 8 were similar between mirtazapine and paroxetine groups. However, patients with mirtazapine exhibited earlier improvement in HARS scores at weeks 1 and 2. Week-by-week GEE models showed that these significant differences in improvement of HARS scores between the two treatment groups were detectable from the first evaluation after the treatment (week 1) and maintained through week 2. There was no difference in the overall frequency of adverse events experienced between the two treatment groups. The most common adverse event in the mirtazapine group was somnolence (n = 8), whereas that in the paroxetine group was gastrointestinal discomfort (n = 9). CONCLUSIONS: Mirtazapine and paroxetine were equally effective and well tolerated for the depressive symptoms in MDD patients with the high level of anxiety symptoms. Mirtazapine was, however, more effective in reducing the anxiety symptoms than paroxetine in the early weeks of treatment, suggesting that mirtazapine may have an earlier-onset action for the anxiety symptoms in MDD patients.

Gray matter deficits in young adults with narcolepsy.

OBJECTIVES: The aim of this study was to investigate gray matter volume changes in narcolepsy. MATERIALS AND METHODS: An optimized voxel-based morphometry was conducted for 17 young adults with a sole diagnosis of human leukocyte antigen DQB(1) 0602 positive narcolepsy with cataplexy (26.6 +/- 5.2 years old) and 17 comparison subjects (24.6 +/- 4.9 years old) using 3 Tesla scanner. Gray matter volumes in the bilateral hypothalamic voxel of interests (VOI) were also calculated. RESULTS: Compared with the comparison subjects, narcoleptic patients had gray matter volume decrease in the right hypothalamus and other regions including subcortical, prefrontal, limbic and occipital areas. Narcoleptic patients also had lower gray matter volume on predefined VOI at the bilateral hypothalamus, which correlated with the Ullanlinna Narcolepsy Scale score. CONCLUSIONS: Current findings suggest that narcoleptic patients have structural abnormalities in hypothalamus, which might be related to the clinical manifestation of narcolepsy with cataplexy.

Reliability and validity of depressive personality disorder.

OBJECTIVE: Depressive personality disorder was introduced into DSM-IV's appendix amid controversy. While that disorder appears to be a reliable and valid one, the authors offer new data about its relationship to major depression, dysthymic disorder, and other personality disorders. METHOD: The authors assessed 54 subjects with early-onset, long-standing mild depressive features for depressive personality disorder, axis I and axis II disorders, family history, and treatment history; they conducted follow-up interviews 1 year after the baseline assessment. Subjects with (N=30) and without (N=24) depressive personality disorder were characterized and compared in terms of those variables. RESULTS: Although depressive personality disorder and dysthymia co-occurred in some subjects, 63% of subjects with depressive personality disorder did not have dysthymia, and 60% did not have current major depression. Although subjects with depressive personality disorder were more likely than the mood disorder comparison group to have another personality disorder, 40% had no such disorder. Contrary to study hypotheses, mood disorder was not more common in first-degree relatives of subjects with depressive personality disorder than in relatives of the comparison group. Subjects with and without depressive personality disorder had similar rates of past treatment with medication and psychotherapy; however, the duration of psychotherapy was significantly longer for subjects with than for those without depressive personality. The depressive personality diagnosis was relatively stable over the 1-year follow-up period. CONCLUSIONS: Depressive personality disorder appears to be a relatively stable condition with incomplete overlap with axis I mood disorders and personality disorders. Further studies are needed to better characterize its treatment response and relationship to axis I mood disorders.

Three-year follow-up of women with the sole diagnosis of depressive personality disorder: subsequent development of dysthymia and major depression.

OBJECTIVE: The authors sought to determine whether subjects with the sole diagnosis of depressive personality disorder are at higher risk for developing dysthymia and major depression than are healthy comparison subjects. METHOD: Eighty-five women with depressive personality disorder who had no comorbid axis I or axis II disorders and 85 age-matched healthy comparison women were initially recruited and reinterviewed 3 years later to evaluate the cumulative incidence rate of dysthymia and major depression. RESULTS: At the 3-year follow-up assessment, the women with depressive personality disorder had a significantly greater odds ratio for developing dysthymia than did the healthy comparison women. The difference in odds ratios for the development of major depression between women with and without depressive personality disorder did not reach statistical significance. CONCLUSIONS: The present study, the first to determine the subsequent development of dysthymia and major depression in subjects with the sole diagnosis of depressive personality disorder, found that subjects with depressive personality disorder had a greater risk of developing dysthymia than did healthy comparison subjects at 3-year follow-up. Findings of the current study also suggest that depressive personality disorder may mediate the effects of a family history of axis I unipolar mood disorders.

Patterns of temperament and character in subjects with obsessive-compulsive disorder.

BACKGROUND: The purpose of this study was to assess the temperament and character patterns of obsessive-compulsive disorder (OCD) patients and to investigate the relationship between patterns of temperament and character and the severity of obsessive-compulsive symptoms. METHOD: The subjects were 40 patients who met DSM-IV criteria for OCD and 40 age-, sex-, and IQ-matched healthy controls. All subjects completed Cloninger's Temperament and Character Inventory. Other instruments included the Yale-Brown Obsessive Compulsive Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory. RESULTS: OCD patients showed significantly higher scores of harm avoidance and lower scores of novelty seeking and self-directedness compared with healthy comparison subjects. In addition, the high harm avoidance and low self-directedness scores are correlated with a greater severity of obsessive-compulsive symptoms in OCD subjects (multiple regression analysis, beta = 0.39, t = 2.54, df = 34, p = .016; beta = -0.41, t = 2.46, df = 34, p = .019, respectively). CONCLUSION: OCD patients had distinct patterns of temperament and character compared with healthy comparison subjects. In addition, these patterns are specifically related to the severity of obsessive-compulsive symptoms.

Structural abnormalities in brain magnetic resonance images of depressed children.

OBJECTIVE: Brain magnetic resonance images (MRIs) of 65 children and adolescents who were hospitalized with depressive disorders (DD) were compared with the brain MRIs of 18 hospitalized psychiatric controls (PC) without a depressive disorder. METHOD: Volumetric analyses were used to measure frontal lobe volumes (FLV), lateral ventricular volumes (VV), and total cerebral volumes (CV) for all subjects. To correct for differences in absolute cerebral volume associated with different body and head size, the ratios of FLV/CV and VV/CV were used to compare differences between the two groups. A multivariate analysis was used to control for the effects of several independent variables (age, sex, diagnosis). RESULTS: Significant differences were seen in the FLV/CV ratio and the VV/CV ratio when the results were compared between the two groups (DD versus PC). The DD group had a significantly smaller FLV/CV ratio (t = 2.148, df = 79, p = .035) and a significantly larger VV/CV ratio (t = -2.093, df = 79, p = .040). CONCLUSION: The findings are consistent with previous reports in depressed adults and may implicate the frontal lobes in the pathogenesis of early-onset depressive disorders.

A brain MRI study in subjects with borderline personality disorder.

BACKGROUND: There have been only a few brain computed tomography imaging studies, with mostly negative findings, in subjects with borderline personality disorder (BPD). This is the first MRI study which evaluated the structural abnormalities of the brain in subjects with the sole diagnosis of BPD. METHODS: Twenty-five subjects with BPD were compared with age-, gender-matched healthy comparison subjects (n=25) on volumes of the frontal lobes, the temporal lobes, the lateral ventricles, and the cerebral hemispheres in brain magnetic resonance imaging. RESULTS: Subjects with BPD had a significantly smaller frontal lobe compared to comparison subjects (multivariate regression analysis, t=2.225, df=46, P=0.031). There were no significant differences in volumes of the temporal lobes, the lateral ventricles, and the cerebral hemispheres between subjects with and without BPD. LIMITATIONS: Strict inclusion and exclusion criteria employed in the present study may make it difficult to generalize our findings. The gray matter and white matter of the brain were not measured separately. Differences in head tilt during image acquisition were not corrected. CONCLUSIONS: The current study reports a smaller frontal lobe volume on brain MRI in subjects with BPD compared with healthy comparison subjects. This finding may serve as a potentially useful biological variable that may allow for subtyping BPD.

Regional atrophy of the corpus callosum in subjects with Alzheimer's disease and multi-infarct dementia.

Regional areas of the corpus callosum (CC) were evaluated in subjects with dementia. The area of the CC and seven distinct subdivisions were measured in subjects with Alzheimer's disease (AD) (n = 162), multi-infarct dementia (MID) (n = 28), and in a healthy comparison group (n = 36). There were significant differences in the regional areas of the CC for both the AD and MID patients relative to values for the comparison subjects. When mildly demented (MMSE > or = 21), subjects with AD had significantly smaller posterior midbody, isthmus, and splenium and subjects with MID had significantly smaller genu relative to comparison subjects. This study reports different patterns of regional CC area loss in subjects with AD and MID.

Family problems and relationships for adults with borderline personality disorder.

The purpose of this study was to compare the perceptions of the family in patients with borderline personality disorder (BPD) to the perceptions of their parents and to those of normative families. We compared ratings on measures of family problems, environment, and relationships from a sample of 21 patients with BPD to ratings by their parents and to standardized ratings from normative families. The results were that (1) patients with BPD perceived their family environment and relationships significantly more negatively than did their parents or the normative families, and (2) parents of a patient with BPD agreed more with each other than with their offspring, with both parents often close to normative standards. We conclude that defensive reactions at the time of initial evaluation probably account for the frequently cited schism between BPD patients' particularly negative reports of their families and the more normative reports by their parents. Clinicians should obtain parental viewpoints as an essential part of evaluating the family environment.

Increased prevalence of white matter hyperintensities in patients with panic disorder.

The aim of the current study is to compare the prevalence, severity and location of cerebral white matter hyperintensities (WMH) between patients with panic disorder (PD) and healthy control subjects. Patients with PD (n = 24) and matched healthy control subjects (n = 24) were scanned using a 3.0 Tesla whole-body magnetic resonance scanner. Axial T2-weighted and fluid-attenuated inversion recovery images were acquired and evaluated for the prevalence, severity and location of WMH using the modified composite scale of Fazekas and Coffey and coded separately for deep and periventricular WMH. Logistic regression analyses were used to assess the association between WMH and the diagnosis of PD. A greater severity of total WMH was associated with a diagnosis of PD in a dose-dependent pattern (odds ratio [OR] = 8.8, P = 0.005 for mild WMH; OR = 27.7, P = 0.007 for moderate to severe WMH). Deep WMH, where most group differences originated, were predominantly located in the frontal region of the brain (n = 16 in PD, n = 1 in control). The current report is the first study to report an increased prevalence of WMH in patients with PD.

The effects of type 1 diabetes on cerebral white matter.

AIM/HYPOTHESIS: Studies investigating the structure, neurophysiology and functional outcomes of white matter among type 1 diabetes patients have given conflicting results. Our aim was to investigate the relationship between type 1 diabetes and white matter hyperintensities. METHOD: We assessed white matter integrity (using magnetic resonance imaging), depressive symptoms and neuropsychological function in 114 type 1 diabetes patients and 58 age-matched non-diabetic controls. RESULTS: Only Fazekas grade 1 and 2 white matter hyperintensities were found among 114 long-duration, relatively young diabetes patients; the severity of lesions did not differ substantially from 58 healthy controls. White matter hyperintensities were not associated with depressive history or with clinical characteristics of diabetes, including retinopathy, severe hypoglycaemia or glycaemia control. CONCLUSIONS/INTERPRETATION: Our data do not support an association between diabetes characteristics and white matter hyperintensities among relatively young type 1 diabetes participants.

Computerized assessment of cognitive impairment in narcoleptic patients.

OBJECTIVES - This study was aimed to investigate the comprehensive range of cognitive performance using the objective computerized assessment system in narcolepsy and age, gender, and IQ-matched healthy comparison. MATERIALS AND METHODS - The cognitive functions of 24 patients with narcolepsy and 24 healthy comparison subjects were assessed. RESULTS - Narcoleptics performed more frequent omission and commission errors in the vigilance test, and more frequent omission errors in the continuous performance test. Narcoleptics' response time was slower than healthy volunteers, and the differences were more exaggerated in more complex tasks. The simple repetitious working performance was more impaired in the narcoleptic subjects than in healthy comparison subjects. Narcolepsy group showed worse performances in the determination unit than the comparison group, and this impairment became more salient in faster stimuli relative to slower ones. CONCLUSIONS - Narcoleptics have deficits of efficiency in attention allocation and execution as well as simple vigilance problem.

Decreased cerebral blood flow of thalamus in PTSD patients as a strategy to reduce re-experience symptoms.

OBJECTIVE: To investigate alterations of regional cerebral blood flow (rCBF) in subjects with post-traumatic stress disorder (PTSD). METHOD: Using [99Tcm]-hexamethyl propylenamino oxime single photon emission computed tomography, the rCBF under resting condition was compared between 19 survivors of the Taegu subway fire with PTSD and 19 comparison subjects. RESULTS: PTSD patients showed a decreased rCBF in the right thalamus and an increased rCBF in the right superior parietal lobe relative to comparison subjects (corrected P < 0.05). The rCBF in the right thalamus positively correlated with the severity of current re-experience symptoms in PTSD subjects. CONCLUSION: Our finding of the thalamic rCBF decrease in PTSD patients may be a strategy to reduce re-experience symptom, by evading the process of external and internal information which can evoke traumatic memory. In addition, the parietal rCBF increase in our PTSD patients might be related to altered information processing in PTSD.

Magnetic resonance spectroscopy for measuring the biodistribution and in situ in vivo pharmacokinetics of fluorinated compounds: validation using an investigation of liver and heart disposition of tecastemizole.

BACKGROUND AND OBJECTIVE: The study of biodistribution and in situ pharmacokinetics is a challenging, but sometimes very important, aspect of premarketing characterization of drugs. We aimed to develop a non-invasive fluorine magnetic resonance (MR) spectroscopic method for the absolute quantitation of a mono-fluorinated compound and of its metabolites in the heart and liver of healthy subjects for this purpose. METHOD: We used fluorine MR spectroscopy (MRS) at 4 T (Tesla) and external standardization in an open label multiple-dose study. Twenty-three healthy adult subjects were enrolled in the study. The surface coil localized fluorine MR spectrum was monitored in the heart and liver at baseline and after oral administration of multiple doses of tecastemizole. Steady-state measurements were made at set time points that depended upon dose, and washout measurements were made only on subjects in which in vivo fluorine signal was observed. RESULTS AND DISCUSSION: At 4 T, under the given experimental conditions, the method had a lower limit of quantitation (LLOQ) of about 2.6 microm and a limit of detection (LOD) of about 0.3 microm for solution state samples (linewidth approximately 15 Hz). The measurement reproducibility was 6.4% using a 50 microm phantom. The effect of MR operator and spectral analyst on the calculated calibration curve slope was small, with inter-rater correlation coefficients of 0.999 and 0.998 respectively. MR signal from fluorine-containing tecastemizole-related moieties was observed in situ only at day 8 in the liver of three of five subjects dosed at 270 mg/day. The average in situ concentration was estimated to be 58+/-22 microm, with an average test-retest reproducibility of 216%. Extrapolating the in vitro results to human measurements, with an approximate linewidth of 250 Hz, predicts in situ LOD and LLOQ values of approximately 6 and 44 microm respectively. However, the human study had a fluorine MRS LOD of approximately 20 microm. The decrease in sensitivity and the increase in variability of the in vivo, in situ measurements compared with the validation study most likely arose from coil placement and incomplete rephasing of the MR signal by the respiratory phase compensation method. CONCLUSION: The measured concentrations were the lowest ever recorded for a multi-dose exogenous mono-fluorinated compound in the human liver using a validated fluorine MR quantitation method. The proposed non-invasive MR method for studying the biodistribution and in situ pharmacokinetics of mono-fluorinated compounds in the liver and heart should have broader application to the development of non-invasive biomarkers.

Patterns of changes in temperament and character inventory scales in subjects with obsessive-compulsive disorder following a 4-month treatment.

OBJECTIVE: The purpose of this study was to assess changes in the temperament and character patterns in subjects with obsessive-compulsive disorder (OCD) following the treatment for obsessive/compulsive and accompanying depressive symptoms. METHOD: Study subjects were 35 patients who met the DSM-IV criteria for OCD. All subjects were assessed with the Temperament and Character Inventory (TCI), the Yale-Brown Obsessive-Compulsive Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory before and after a 4-month treatment. RESULTS: Harm Avoidance (HA) scores in OCD subjects before treatment significantly decreased after treatment. However, the Self-Directedness scores, which were significantly lower than healthy comparison subjects before treatment, did not change. In addition, Reward Dependence scores in OCD subjects, which were not significantly different from healthy comparison subjects before treatment, significantly increased after treatment. CONCLUSION: The TCI pattern of untreated OCD subjects (high HA and low Self-Directedness, relative to healthy comparison subjects) and the decrease of HA scores and no change in Self-Directedness scores following a successful treatment suggest that temperaments are more amenable to treatment than characters.